The CDC estimates that in 2010 over 216 million clinical episodes of malaria occurred worldwide with over 665,000 deaths (with over 86% of deaths being that of children). Over 3.3 billion of the world's populations live in areas where malaria is transmitted and although malaria is not a current threat in the US, the transmission vector for the parasite, Anopheles mosquitoes, is widely prevalent and there remains a constant risk of reintroduction of malaria into the US. Emergence of drug-resistance has been an on-going problem in malaria treatment and even the relatively newly introduced artemisinin-based combination therapies are beginning to develop resistance. Given the global toll of malaria and the continued development of drug resistance, it is important to identify new chemical entities that act via different modes of action and which provide therapeutic options for the treatment of drug-resistant malaria. Natural products have long been an important source of anti-malarial agents with quinine and its synthetic derivatives, artemisinin and its derivatives, all being front line treatments for malaria. Harbor Branch Oceanographic Institute's Marine Biomedical & Biotechnology Research Group (HBOI) has had an on-going marine natural products research program since 1984 and has published reports on over 150 novel bioactive compounds and greater than 100 patents have issued to protect these discoveries. HBOI has a unique frozen repository of marine macro-organisms (many derived from deep-water habitats) and a library of highly enriched fractions derived from these organisms that contain a wide variety of chemical classes and structures. In a pilot project conducted in collaboration with Dr. Chakrabarti of the University of Central Florida (UCF), a sub-set of the HBOI enriched fraction library was screened resulting in the identification of 165 fractions from 85 organisms that reproducibly inhibit the drug resistant Dd2 strain of Plasmodium falciparum at concentrations lower than 5 g/mL. Four series of compounds have already been identified and LC-MS and NMR analysis suggests that many of the remaining active organisms contain novel natural products and are excellent leads for the identification of new chemical scaffolds that can inhibit the malaria parasite. The overarching goal of this collaborative project between Amy Wright of HBOI and Debopam Chakrabarti of UCF is to identify marine invertebrate derived natural products that have utility in the development of new treatments for malaria. The specific goal of this project is to purify and define the structures of the active compounds present in the lead organisms found through our earlier screening project and to further characterize their biological and chemical properties.